Characterization of the immunosuppressive environment induced by larval Echinococcus granulosus during chronic experimental infection.

ABSTRACT

The larval stage of Echinococcus granulosus causes the chronic infection known as cystic echinococcosis, deploying strong inhibitory mechanisms on host immune responses. Using experimental intraperitoneal infection in C57BL/6 mice, we carried out an in-depth analysis of the local changes in macrophage populations associated with chronic infection. In addition, we analyzed T cells and relevant soluble mediators. Infected animals showed an increase in local cell numbers, mostly accounted for by eosinophils, T cells, and macrophages. Within macrophage populations, the largest increases in cell numbers corresponded to resident large peritoneal macrophages (LPM). Monocyte recruitment appeared to be active, as judged by the increased number of monocytes and cells in the process of differentiation towards LPM, including small (SPM) and converting peritoneal macrophages (CPM). In contrast, we found no evidence of macrophage proliferation. Infection induced the expression of M2 markers in SPM, CPM, and LPM. It also enhanced the expression of the co-inhibitor PD-L1 in LPM, SPM, and CPM and induced the co-inhibitor PD-L2 in SPM and CPM. Therefore, local macrophages acquire M2-like phenotypes with probable suppressive capacities. Regarding T cells, infection induced an increase in the percentage of CD4+ cells that are PD-1+, which represent a potential target of suppression by PD-L1+/PD-L2+ macrophages. In possible agreement, CD4+ T cells from infected animals showed blunted proliferative responses to in vitro stimulation with anti-CD3. Further evidence of immune suppression in the parasite vicinity arose from the observation of an expansion in FoxP3+ CD4+ regulatory T cells and increases in the local concentrations of the anti-inflammatory cytokines TGF-ß and IL-1Ra.